Chloro-substituted sucrose compounds

ABSTRACT

A method of sweetening a substance comprises incorporating therein a mono- or poly- chloro, mono- or poly- deoxy sucrose derivative having chlorine atoms in selected combinations of positions 4,6,1&#39;- and 6&#39;- of the sucrose molecule. The compounds are many times sweeter than sucrose and are formulated as ingestible products, such as foodstuffs and beverages; oral compositions, such as toothpaste and chewing gum; or sweetening compositions, such as tablets, for addition to beverages, etc.

This is a divisional of U.S. patent application Ser. No. 755,661, filedDec. 30, 1976, now U.S. Pat. No. 4,435,440.

This invention relates to sweeteners for ingestible products, oralcompositions and sweetening compositions.

By an "ingestible product" there is meant one which in the ordinarycourse of use is intended to be swallowed, for instance a foodstuff orbeverage, or an orally administered pharmaceutical composition. By an"oral composition" there is meant one which in the ordinary course ofuse is not intended to be ingested as such, but is taken into the mouthfor the treatment of the throat or buccal cavity, for instance atoothpaste, tooth powder, mouth wash, gargle, troche, dental lotion orchewing gum. By a "sweetening composition" there is meant a compositionwhich is not itself taken orally, either to be ingested or held in themouth, but instead is intended to be added to other ingestible productsor oral compositions to render them sweet or to increase theirsweetness.

Although sucrose is still the most widely used sweetening agent, manyefforts have been made to find substantially sweeter alternatives whichcould be used when it is desired to combine a high degree of sweetnesswith a low calorie content and/or a low risk of dental caries, forexample in dietetic products and in the manufacture of soft drinks. Thetwo most successful non-sucrose sweeteners (that is to say sweetenerscomprising a compound other than sucrose itself) to data have beensaccharin and cyclamate, having respectively about 200 and about 30times the sweetening powder of sucrose, but the use of these sweeteners,particularly cyclamate, has recently been restricted or banned in somecountries because of doubts abou their safety. Saccharin also suffersfrom the disadvantage of an unpleasantly bitter after-taste which can bedetected by many people.

More recently, many other non-sucrose sweeteners have been investigated,some of natural origin and others synthetic, covering a wide range ofchemical structures. These compounds have included proteins, such asmonellin, thaumatin and miraculin, dipeptides such as aspartame, anddihydrochalcones such as neohesperidin dihydrochalcone. However, apartfrom the difficulties of synthesizing or extracting such sweeteners,they do not necessarily possess the same quality of sweetness assucrose: in particular, as compared with sucrose, the sweetness may beslow in onset and relatively lingering, and there may be aliquorice-like or other after-taste, making the sweetener unsuitable asa direct replacement for sucrose unless these differences can be masked.

Although numerous sweeteners of widely diverse chemical structures havenow been investigated, it is significant to note that sweetnesssubstantially greater than that of sucrose has not been discovered inany derivative of sucrose or in any other carbohydrate; when anintensely sweet substance has been discovered, such as saccharin,cyclamate and the other non-sucrose sweeteners already mentioned, itsstructure has always been radically different from that of sucrose.Indeed, it is known tht the presence of some substituents on the sucrosemolecule can, in fact, destroy its sweetness and even impart a bittertaste.

Most surprisingly, and in complete contrast to previous knowledge abournon-sucrose sweeteners, we have now discovered that certain derivativesof sucrose and of a sucrose isomer are very much sweeter than sucroseitself, their sweetness being comparable in intensity with that ofsaccharin, but having a quality similar to that of sucrose.

According to the present invention we provide as sweetening agentssucrose derivatives of the general formula ##STR1## in which R¹represents a hydroxy group or a chlorine atom; R² and R³ respectivelyrepresent a hydroxy group and a hydrogen atom, a chlorine atom and ahydrogen atom, or a hydrogen atom and a chlorine atom, the 4-positionbeing in the D-configuration;

R⁴ represents a hydroxy group; or, if at least two of R¹, R², R³ and R⁵represent chlorine atoms, R⁴ represents a hydroxy group or a chlorineatom; and

R⁵ represents a hydroxy group; or, if at least one of R¹, R² and R³represents a chlorine atom, R⁵ represents a hydroxy group or a chlorineatom;

provided that at least one of R¹, R², R³ and R⁵ represents a chlorineatom.

The compounds of formula (I) can be used as sweetening agents in anyconventional way, including the sweetening of "ingestible products" (aspreviously defined), for example foodstuffs, beverages and orallyadministered pharmaceutical compositions, and of "oral compositions" (aspreviously defined), for example toothpastes, chewing gums and mouthwashes. They can also be used, with conventional liquid or solidextenders and carriers, in "sweetening compositions" (as previouslydefined).

The extender or carrier comprises any suitable vehicle for the sucrosederivative of the general formula (I) so that it can be formulated in acomposition which can conveniently be used for sweetening otherproducts, for example granules, tablets or drops. The extender orcarrier may thus include, for example, conventional water-dispersibletabletting ingredients, such as starch, lactose and sucrose itself;low-density bulking agents to provide a granular sweetening compositionhaving a volume per unit sweetness equivalent to that of sucrose, forexample, spray dried maltodextrins; and aqueous solutions containingadjuvants such as stabilizing agents, colouring agents andviscosity-adjusting agents.

Beverages, such as soft drinks, containing a sucrose derivative of thegeneral formula (I) may be formulated either as sugar-free dieteticproducts, or "sugar-reduced" products containing the minimum amount ofsugar required by law. In the absence of sugar it is desirable to addfurther agents to provide a "mouth feel" similar to that provided bysugar, for example pectin or a vegetable gum. For example, pectin may beadded at a level of from 0.1 to 0.15% in a bottling syrup.

A number of compounds of the general formula (I) which may be usedaccording to the present invention are shown in the following Table.

                  TABLE                                                           ______________________________________                                         ##STR2##                                                                                                        Approximate                                Compound No.                                                                             R.sup.1                                                                             R.sup.2                                                                             R.sup.3                                                                           R.sup.4                                                                           R.sup.5                                                                           sweetness (x sucrose)*                     ______________________________________                                        1          Cl    OH    H   OH  OH  20                                         2          OH    H     Cl  OH  OH  5                                          3          Cl    H     Cl  OH  OH  600                                        4          Cl    OH    H   OH  Cl  500                                        5          Cl    H     Cl  OH  Cl  2000                                       6          OH    H     Cl  Cl  Cl  4                                          7          Cl    OH    H   Cl  Cl  100                                        8          Cl    H     Cl  Cl  Cl  200                                        9          Cl    Cl    H   Cl  Cl  100                                        ______________________________________                                         *Sweetness Evaluation                                                         The sweetness is evaluated in aqueous solution, by comparison with a 10%      by weight aqueous solution of sucrose. The results were obtained from a       small taste panel and are therefore, not statistically accurate, but          indicate the approximate order of sweetness.                             

The compounds in Table 1 are as follows (the systematic nomenclature isgiven first, followed by a trivial name based on "galactosucrose" inthose cases where a 4-chloro substituent is present):

1. 1'-chloro-1'-deoxysucrose

2. 4-chloro-4-deoxy-α-D-galactopyranosyl-β-D-fructofuranoside [i.e.4-chloro-4-deoxygalactosucrose]

3.4-chloro-4-deoxy-α-D-galactopyranosyl-1-chloro-1-deoxy-β-D-fructofuranoside[i.e. 4,1'-dichloro 4,1'-dideoxygalactosucrose]

4. 1',6'-dichloro-1',6'-dideoxysucrose

5.4-chloro-4-deoxy-α-D-galactopyranosyl-1,6-dichloro-1,6-dideoxy-.beta.-D-fructofuranoside[i.e. 4,1',6'-trichloro-4,1',6'-trideoxygalactosucrose]

6.4,6-dichloro-4,6-dideoxy-α-D-galactopyranosyl-6-chloro-6-deooxy-.beta.-D-fructofuranoside[i.e. 4,6,6'-trichloro-4,6,6'-trideoxygalactosucrose]

7. 6,1',6'-trichloro-6,1',6'-trideoxysucrose

8.4,6-dichloro-4,6-dideoxy-α-D-galactopyranosyl-1,6-dichloro-1,6-dideoxy-β-D-fructofuranoside[i.e. 4,6,1',6'-tetrachloro-4,6,1',6'-tetradeoxygalactosucrose]

9. 4,6,1',6'-tetrachloro-4,6,1',6'-tetradeoxysucrose.

From Table 1 it may be seen that chloro substituents at the 4-, 1'- and6'-positions are effective in inducing sweetness. A combination of twosuch substituents is synergistic and in general raises the sweetness byapproximately one order of magnitude rather than being simply additive.Thus, for example, a 1'-chloro substituent by itself gives a sweetnessof 20× and a 4β-chloro substituent by itself a sweetness of 4×. However,a 4,1'-dichloro combination gives a sweetness of 600× and a1',6'-dichloro combination gives a sweetness of 500×. Similarly, acombination of all three chloro substituents raises the sweetness byapproximately one more order, the 4,1',6'-trichloro derivative having asweeteness of 2000×. (All sweetnesses expressed as multiples of that ofsucrose).

In contrast, a 6-chloro substituent is disadvantageous, and causes areduction in sweetness by antagonising the action of the othersubstituents. For this reason, a 6-chloro substituent--R⁴ in formula(I)--may only be present when at least two other chloro substituents arepresent.

In general, the 6-chloro-substituted compounds are not preferred forthis reason--the most sweet compounds containing 4,1'- and 6'-chlorosubstituents.

The remarkable sweetness of the compounds of formula (I) is combinedwith an LD₅₀ (lethal dose 50%) which, in the case of compound 5 in Table1, for example, is in excess of 16 g/kg in mice, that being the largestdose which can be administered in practice.

Many of the compounds of the general formula (I) are known and can beprepared by the synthetic routes disclosed in the chemical literature.However, none of the known compounds has previously been recognised aspossessing any useful sweetness.

Thus, Compound 5 is reported in Carbohyd. Res., 40, (1975), 285;Compound 6in Carbohyd. Res., 44, (1975), 37; and Compound 7 in Carbohyd.Res., 25, (1972), 504 and ibid 44, (1975), C12-C13. Compound 2 isreported in Carbohyd. Res., 40, (1975), 285-298.

All of the compounds of the general formula (I), both new and old, maybe prepared by reaction of a sucrose ester, having free hydroxy groupsin the portions required to be chlorinated, with sulphuryl chloride toobtain the corresponding chlorosulphate derivative. This, on treatmentwith a source of chloride ions such as lithium chloride, in an amidesolvent such as hexamethyl phosphoric triamide, yields the chlorinatedsucrose water. Hydrolysis of the chloro-ester, e.g. using sodiummethoxide in dry methanol, then liberates the free chlorosucrose. Thereaction with sulphuryl chloride is conveniently effected at a reducedtemperature in an inert solvent in the presence of a base, for example,chloroform containing pyridine.

A similar method can be used for further chlorinating an alreadychlorinated sucrose derivative.

In general 4-chloro-sucrose derivatives can be obtained by reaction ofthe 4-chloro-galactosucrose analogue with a source of chloride ions atan elevated temperature, e.g. 100°-150° C., preferably in the presenceof a catalytic amount of iodine.

The following Examples illustrate the invention further (temperaturesare given in degrees centigrade).

EXAMPLE 1 1'-chloro-1'-deoxysucrose (Compound 1) (a)1'-chloro-1'-deoxysucrose hepta-acetate

A solution of 2,3,4,6,3',4',6'-hepta-O-acetylsucrose (2 g) in a mixtureof pyridine (10 ml) and chloroform (30 ml) was treated with sulphurylchloride (2 ml) at -75° for 45 minutes. The reaction mixture was takenup in ice-cold sulphuric acid (10%, 200 ml) and dichloromethane (200 ml)and shaken vigorously. The organic layer was then successively washedwith water, aqueous sodium hydrogen carbonate and water, and then dried(Na₂ SO₄). The solution was concentrated and then extracted with ether.The insoluble material was filtered off and the filtrate concentrated togive the corresponding 1'-chlorosulphate derivative (2.1 g).

This syrupy residue (2 g) was then treated with lithium chloride (2 g)in hexamethyl phosphoric triamide (HMPA) (10 ml) at 90° for 24 hours.The reaction mixture was poured into ice-water, and the precipitateformed was collected, washed with water, and taken up in ether. Theorganic layer was dried over sodium sulphate, concentrated and elutedfrom a silica gel column with ether--light petroleum (1:1) to give the1'-chloro hepta-acetate as an amorphous powder [α]_(D) +55.0° (c 1.2,CHCl₃); n.m.r. data: τ 4.29 (d, J₁,2 3.5 Hz, H-1); 5.11 (dd, J₂,3 10.0Hz, H-2); 4.56 (t, J₃,4 9.5 Hz, H-3); 4.94 (t, J₄,5 9.5 Hz, H-4); 4.32(d, J_(3'),4' 6.5 Hz, H-3'); 4.60 (t, J_(4'),5' 6.5 Hz, H-4'); 7.84-8.01(7 Ac). Mass spectral data: [(a) indicates ions due to hexapyranosylcation and (b) a 3:1 doublet (1Cl) due to ketofuranosyl]: m/e 331 a, 307b, 187 b, 169 a, 145 b, 109 a.

Analysis calculated for C₂₆ H₃₅ ClO₁₇ : C,47.7; H,5.4; Cl,5.4%; Found:C,47.5; H,5.6; Cl,5.7%.

(b) 1'-chloro-1'-deoxysucrose

A solution of the above intermediate (1 g) in dry methanol (10 ml) wastreated with a catalytic amount of M sodium methoxide in methanol atroom temperature for 5 hours. T.l.c. (dichloromethane-methanol, 3:1)showed a slow-moving product. The solution was deionized by shaking withAmberlyst -15 (a polystyrene sulphonic acid resin), in H⁺ form,concentrated, and purified by shaking an aqueous solution of the syrupwith petrol. The aqueous layer was then concentrated and dried undervacuum to give 1'-chloro-1'-deoxysucrose [α]_(D) +57.8° (c 0.7, water).

Analysis calculated for C₁₂ H₂₁ ClO₁₀ : C, 39.9; H, 5.9; Cl, 9.8%;Found: C, 39.7; H, 6.1; Cl, 9.7%.

EXAMPLE 2 4,1'-dichloro-4,1'-dideoxygalactosucrose (Compound 3) (a)2,3,6-Tri-O-acetyl-4-chloro-4-deoxy-α-D-galactopyranosyl-3,4-di-O-acetyl-6-O-benzoyl-1-chloro-1-deoxysucrose

A solution of 2,3,6,3',4'-penta-O-acetyl-6'-O-benzoylsucrose (2 g) in amixture of pyridine (10 ml) and chloroform (30 ml) was treated withsulphuryl chloride (2 ml) at -75° for 45 minutes. The reaction mixturewas poured into ice-cold sulphuric acid (10%, 200 ml) with vigorousshaking and then extracted with dichloromethane. The organic layer waswashed successively with water, aqueous sodium hydrogen carbonate, andwater, and dried (Na₂ SO₄). The solution was concentrated and extractedwith ether. The insoluble material was filtered off and the filtrateconcentrated to give the chlorosulphate (2.1 g). This intermediate wasthen treated with lithium chloride as in Example 1 to give theabove-named chloro intermediate.

(b)4-chloro-4-deoxy-α-D-galactopyranosyl-1-chloro-1-deoxy-β-D-fructofuranoside

A solution of the above intermediate from (a) (1 g) in dry methanol wastreated with a catalytic amount of M sodium methoxide in methanol atroom temperature for 5 hours. T.l.c. (dichloromethane-methanol, 4:1)showed one product. The reaction was worked up as described in Example1(b) to give the title product as a syrup, [α]_(D) +49.6° (c 0.7,water).

Analysis calculated for C₁₂ H₂₀ Cl₂ O₉ : C,38.0; H, 5.3; Cl, 18.7%;Found: C, 35.7; H, 6.0; Cl, 20.4%.

By a similar method 1',6'-dichloro-1',6'-dideoxysucrose (Compound 4) wasprepared: [α]_(D) +67°(c 1.0, methanol).

Analysis calculated for C₁₂ H₂₀ Cl₂ O₉ : C, 38.0, H, 5.3; Cl, 18.7%;Found: C, 37.7; H, 5.2; Cl, 17.1%.

Hexa-acetate--white solid foam, [α]_(D) +51.7°(c 1.0, CHCl₃) Massspectrometry m/e 331 and 283 (2 Cl). Characterized by reductivedehalogenation with Raney Nickel, H₂ and KOH to 1',6'-dideoxysucrosehexaacetate--a thick colourless syrup; [α]_(D) +25.5°(c 1.0, CHCl₃). 100Hz N.M.R. (C₆ D₆ τ values)--H-1, 4.36 d (J₁,2 3.5 Hz); H-2, 4.99 q (J₂,310.5 Hz); H-3, 4.17 t (J₃,4 10.0 Hz); H-4, 4.71 t (J₄,5 10.0 Hz); H-1',8.58 s; H-6', 8.60 d.

EXAMPLE 31,6-dichloro-1,6-dideoxy-β-D-fructofuranosyl-4,6-dichloro-4,6-dideoxy-α-D-galactopyranoside(Compound 8)

A solution of 6,1',6'-trichloro-6,1',6'-trideoxysucrose (3 g) inpyridine (70 ml) was treated with sulphuryl chloride (35 ml) in drychloroform (100 ml) at -75° for 3 hours. The solution was stirred at 0°to <5° for 2 hours and then at room temperature for 24 hours. Thereaction mixture was then diluted with dichloromethane (100 ml) andwashed successively with ice-cold sulphuric acid (10%, 250 ml), water,aqueous sodium hydrogen carbonate, and water. The organic layer wasdried over sodium sulphate and concentrated to give a syrup. The syrupyresidue was dissolved in methanol (100 ml) and dechlorosulphated bymeans of excess barium carbonate and a catalytic amount of sodiumiodide. The inorganic residue was filtered off and the filtrateconcentrated to a syrup. T.l.c. (chloroform--methanol, 4:1) showed the4,6,1',6'-tetrachloro-4,6,1',6'-tetradeoxygalactosucrose as the majorproduct. A fast-moving minor product, probably a pentachloro derivative,was also observed. Purification on a column of silica gel, usingchloroform--acetone (5:1) gave the tetrachloro derivative in 90% yield.

Precisely equivalent results were obtained by repeating the aboveprocedure but starting from 1',6'-dichloro-1',6'-dideoxysucrose or1'-chloro-1'-deoxysucrose, instead of the6,1',6'-trichloro-6,1',6'-trideoxysucrose.

[α]_(D) +89°(c 1.0, methanol). Mass spectroscopy: m/e 199 (2-Cl).

Tetra-acetate--white solid foam, [α]_(D) +98.5°(c 1.0, CHCl₃). 100 MHzN.M.R. (CDCl₃, τ values)-4.28 d (H-1), 5.25 q (H-4), 4.30 d (H-3'), 4.55t (H-4')J₁,2 3.5 Hz; J₃,4 3.0 Hz; J₄,5 1.5 Hz; J_(3'),4' 6.5 Hz;J_(4'),5' 6.5 Hz. Mass spectrometry m/e 283 (2 Cl).

Tetra-mesylate--very pale yellow crystals from dichloromethane--ethanol;m.p. 120°-121°; [α]_(D) +65.5°(c 1.0, CHCl₃). 100 MHz N.M.R. (CDCl₃, τvalues) H-1 4.18 d (J₁,2 3.5 Hz); H-2 5.06 q (J₂,3 10 Hz); H-3 4.77 q(J₃,4 3.5 Hz); H-4 5.20 q (J₄,5 1.5 Hz); H-3' 4.39 d (J_(3'),4' 7.0 Hz);H-4' 4.65 t (J_(4'),5' 7.0 Hz); Mass spectrometry m/e 355 (2 Cl).

EXAMPLE 4 4,6,1',6'-tetrachlorosucrose (Compound 9)

To a solution of4,6,6'-trichloro-4,6,6'-trideoxy-2,3,3',4'-tetra-O-acetylgalactosucrose1'-O-monomesitylenesulphonate (1 g) in D.M.F. (15 ml) was added excessof lithium chloride (2 g) and a catalytic amount of iodine (50 mg) andthe mixture was heated at 140°-145° in an oil-bath for 18 hours. T.l.c.(benzene--ethylacetate 3:1) indicated the presence of a major productmoving faster than the starting material. The reaction mixture wascooled, poured into ice-cold water and then extracted with ethylacetate. The organic extract was washed thoroughly, first with 5% sodiumthiosulphate solution and then with water, and dried. The ethyl acetatewas evaporated off and the residue was treated with methanol containinga catalytic amount of sodium methoxide.

T.l.c. (chloroform/acetone/methanol/water, 57:20:20:3) now showed thepresence of a faster-moving minor product and a slower-moving majorproduct--both having very similar mobilities and the lattercorresponding to 4,6,1',6'-tetradeoxy-galactosucrose (Compound 8) (mixedt.l.c.). The mixture was fractionated over a column of silica gel usingchloroform-methanol (10:1) as eluent. Although complete separation wasnot achieved because of the close mobilities of the two components, thefirst few fractions contained4,6,1',6'-tetrachloro-4,6,1',6'-tetradeoxy-sucrose which was obtained asa white solid [α]_(D) +45°(c 1.0, MeOH). The structure was confirmed byn.m.r. and mass spectrometry of the following derivatives:

Tetraacetate--syrup, [α]_(D) +30.5°(c 1.0 CHCl₃) N.M.R. (C₆ D₆ τvalues)--H-1, 4.39 d (J₁,2 4.35 Hz); H-2,5.14 q (J₂,3 10 Hz); H-3, 4.27t (J₃,4 10 Hz); H-4, 6.1 t (J₄,5 10 Hz); H-3', 4.20 d (J_(3'),4' 9.6Hz); H-4', 4.62 t (J_(4'),5' 6.0 Hz).

Tetra-mesylate--white crystalline compound m.p. 187°(dichloromethane--methanol) [α]_(D) +29.9°(c 1.0, acetone).

EXAMPLE 5 Sweetening tablets for beverages, etc.

    ______________________________________                                        Each tablet contains:                                                         ______________________________________                                               Compound 3                                                                              8 mg                                                                or Compound 5                                                                           2 mg                                                         ______________________________________                                    

together with a dispersable tablet base (ca. 60 mg) containing sucrose,gum arabic and magnesium stearate, and is equivalent in sweetness toabout 4.5 g sucrose.

EXAMPLE 6 Bulked sweetener

A bulked sweetener having the same sweetness as an equivalent volume ofsucrose (granulated sugar) is prepared by mixing the followingingredients and spray-drying to a bulk density of 0.2 g/cc:

    ______________________________________                                        maltodextrin solution containing dry weight                                                             222.2  g                                            Compound 3                1.7    g                                            (or Compound 5            0.5    g).                                          ______________________________________                                    

The resulting composition has a sweetening power equivalent toapproximately 2 kilograms of sugar.

EXAMPLE 7 Reduced calorie cola drink containing sugar

    ______________________________________                                        Ingredients to prepare 100 ml bottling syrup:                                 ______________________________________                                        Compound 3             80    mg                                               (or Compound 5         20    mg)                                              Sugar                  60    g                                                Benzoic acid           35    mg                                               Phosphoric acid (conc.)                                                                              1     ml                                               Cola flavour           1.1   ml                                               Colour                  ad-lib.                                               ______________________________________                                    

Make up to 100 ml with mineral water. This syrup may then be added in 25ml doses to carbonated 225 ml aliquots of chilled mineral water.

EXAMPLE 8 Carbonated low calorie lemonade (sugar-free) Ingredients toprepare 100 ml syrup:

    ______________________________________                                        Compound 3            100    mg                                               (or Compound 5        19     mg)                                              Benzoic acid          35     mg                                               Citric acid (dry base)                                                                              1.67   g                                                Lemon essence         0.8    g                                                ______________________________________                                    

Make up to 100 ml in mineral water. This syrup can be added in 25 mldoses to 225 ml aliquots of carbonated chilled mineral water.

EXAMPLE 9 Toothpaste

    ______________________________________                                                         % by weight                                                  ______________________________________                                        Dibasic calcium phosphate                                                                         50%                                                       Glycerol            20%                                                       Sodium lauryl sulphate                                                                           2.5%                                                       Spearmint oil      2.5%                                                       Gum tragacanth     1.0%                                                       Compound 3         0.03%                                                      Water              23.97%                                                     ______________________________________                                    

The ingredients are mixed to produce a spearmint flavoured toothpaste ofacceptable sweetness but free from sugar or saccharin.

EXAMPLE 10 Chewing Gum

    ______________________________________                                                         part by weight                                               ______________________________________                                        Polyvinyl acetate  20                                                         Butyl phthalylbutylglycolate                                                                     3                                                          Polyisobutylene    3                                                          Microcrystalline wax                                                                             2                                                          Calcium carbonate  2                                                          Flavouring/aroma   1                                                          Compound 3           0.07                                                     Glucose            10                                                         ______________________________________                                    

The above chewing gum base can be cut into conventional tablets orstrips.

The 1',6'-dichloro derivative can be prepared by reacting sucrose withmesitylenesulphonyl chloride, separating the desired dimesitylenesulphonates from the mixture of substituted sucroses by, for example,chromatography and replacing the mesitylenesulphonyloxy substituentswith chlorine atoms by reaction with lithium chloride after protectingthe remaining free hydroxyl groups by esterification, for example, withacetic anhydride.

From the above noted mixtures of mesitylenesulphonate substitutedsucroses, the 6,1',6' trisubstituted sucrose derivate, which is presentin relatively large proportions, can be separated. This tri-substitutedderivative can, in a manner similar to that noted above, be converted tothe 6,1',6'-trichloro-substituted derivative. From thistrichloro-substituted derivative, the desired tetrachloro-substitutedderivative can be prepared in good yields, after de-esterificationfollowed by reaction with sulphuryl chloride at low temperatures.

Other potential ways of preparing the 1',6'-dichlorosucrose derivativesof the invention include chlorinating the 4,6-benzylidene derivatives ofsucrose, while other potential ways of preparing the4,6,1',6'-tetrachlorosucrose derivatives include reacting sucrose withmesitylenesulphonyl chloride under more severe conditions to promote theformation of the tetra-substituted derivative followed by replacing thefour mesitylenesulphonyloxy substituents with chlorine atoms.

The preparation of the chloro-derivatives of sucrose by these methodswill now be illustrated by the following Examples.

EXAMPLE 11

Sucrose was treated with mesitylenesulphonyl chloride (3 mole) inpyridine at -5° C. for 6 days to give a major product1',6,6'-tri-O-mesitylenesulphonylsucrose as described by L. Hough, S. P.Phadnis and E. Tarelli, Carbohydrate Research, 1975, 44, C 12 and C 13to which reference is directed. Thus, concentration of the reactionmixture and conventional extraction of the residue into chloroform gave6-O-mesitylenesulphonyl-α-D-glucopyranosyl-1,6-di-O-mesitylenesulphonyl-β-D-fructofuranoside(melting point 135° C. [dec]). More of this compound was obtained fromthe mother liquors after chromatography on silica gel. This compound wasthen converted into6-chloro-6-deoxy-α-D-glucopyranosyl-1,6-dichloro-1,6-dideoxy-62-D-fructofuranoside by treatment of the penta-acetate with lithiumchloride in N,N-dimethylformamide containing a trace of iodine at 140°C. for 18 hours (melting point 127° C. from ethanol, [α]_(D) +58°; c 1chloroform).

EXAMPLE 12

The mother liquors from the concentration and extraction step of Example11 were subjected to chromatography on silica gel to give a mixture ofisomeric disulphonate. Upon the addition of 2-propanol or ethanol, the1',6'-dimesitylenesulphonate crystallized and was identified [meltingpoint 129° to 130° C.; [α]_(D) +67.5° (methanol)].

The dimesitylenesulphonate was acetylated by treatment with aceticanhydride and then reacted at 140° C. for 18 hours with lithium chloridein N,N-dimethylformamide containing a trace of iodine to give the1',6'-dichloride in a high yield. This dichloride was characterized by ¹H-n.m.r., mass spectrometry and by conversion to the corresponding1',6'-dideoxy compound.

EXAMPLE 13

The 6,1'-6'-tri-O-mesitylenesulphonylsucrose prepared in Example 11 wasacetylated by treatment with acetic anhydride and reacted at 140° C. for18 hours with lithium chloride in N,N-dimethylformamide containing atrade of iodine to give the 6,1',6'-trichloride.

This trichloride was then de-O-acetylated by treatment with methanolicsodium methoxide and the product (1 mole) was dissolved in pyridine,cooled to -40° C. and a solution of sulphuryl chloride (10 mole) inchloroform was added dropwise. The reaction mixture was allowed to warmto 0° C., kept at this temperature for 24 hours, after which it waspoured into ice-cold, 10% sulphuric acid. The mixture was extracted withchloroform, the extract washed with aqueous sodium bicarbonate, thenwater and dried with MgSO₄. Evaporation of the chloroform, followed byde-chlorosulphation in methanol using sodium iodide and sodium carbonateas described by L. Hough, S. P. Phadnis and E. Tarelli in CarbohydrateResearch, 1975, 44, 37-44, gave the crude4,6,1',6'-tetrachlorogalactosucrose. This was then purified byconversion to the tetra-O-acetate, followed by column chromatography andde-O-acetylation.

The desired tetrachloro compound was characterized by ¹³ C-n.m.r., massspectrometry and by conversion into the tetramethanesulphonate [meltingpoint 120°-121° C.; [α]_(D) +65.5°(c 1 chloroform)].

We claim:
 1. 1'-chloro-1'-deoxysucrose. 2.4-chloro-4-deoxy-α-D-galactopyranosyl-1-chloro-1-deoxy-β-D-fructofuranoside.3. 4,6,1',6'-tetrachloro-4,6,1',6'-tetradeoxysucrose. 4.1',6'-dichloro-1',6'-dideoxysucrose. 5.4,6,-dichloro-4,6,-dideoxy-α-D-galactopyranosyl-1,6,-dichloro-1,6-dideoxy-β-D-fructofuranoside.